Project Summary/Abstract The discovery and development of new methods for the preparation and use of organic compounds has considerable impact upon how drugs are discovered and synthesized. One overall objective of this application is the development of catalytic C-H bond activation and carbon-carbon bond formation for the convergent assembly of amine containing compounds present in 84% of small-molecule drugs. Methods for the preparation of the subset of nitrogen heterocycles present in 59% of drugs are emphasized. Efficient syntheses of these compound classes will be accomplished by C-H functionalization methods. One example is stereoselective, catalytic two- and three-component C-H bond additions to C=O/C=N bonds to provide diverse amine and alcohol products that in situ can be transformed into more complex, drug-relevant heterocycles. New earth abundant Co(III) catalysts will be developed and studied for these transformations. Another example is efficient syntheses of diverse piperidines, the heterocycle class with the highest frequency of occurrence in drugs, by regio- and stereoselective elaboration of highly substituted 1,2-dihydropyridines generated in situ by one step C-H bond functionalization/electrocyclization cascades. New methods will also be achieved to prepare bridged and fused bicyclic and multicyclic piperidines, including pharmaceutical agents. Innovative new types of reactivity will be explored in C-H bond functionalization and subsequent transformations. These significant studies will enable the more rapid preparation of analogs in drug discovery efforts and reduced cost and waste in drug production due to; (1) the ubiquitous presence of C-H bonds in organic compounds, (2) the very high functional group compatibility of the Rh and Co catalysts used, and (3) the importance of the compound classes prepared. The second overriding objective is the development and use of potent and selective enzyme inhibitors discovered through substrate-based fragment approaches. Orally available inhibitors of cruzain, an essential protease of the parasite responsible for Chagas disease, have been developed as have near-IR quenched activity-based inhibitors of cathepsin S for imaging in vivo. The first inhibitors of Striatal-Enriched Phosphatase (STEP), a protein tyrosine phosphatase (PTP) implicated in a number of neurodegenerative diseases, including Alzheimer's disease (AD), will be advanced. Structure- based optimization will be carried out using the first x-ray structures of STEP inhibitor complexes. Reversible covalent inhibitors developed to recapitulate known physiological means of PTP regulation will also be advanced. This innovative platform for PTP inhibition has already resulted in compounds that reverse cognitive dysfunction in AD mouse models. The substrate fragment approach will also be applied to the increasingly prominent class of protein post-translational modification enzymes, the protein arginine deiminases (PADs), for which little inhibitor development has so far been carried out. This new and innovative approach has already resulted in PAD3 selective small molecule inhibitors and will be applied to the other PAD isozymes.